Stereochemical Determination

One may determine whether additions to alkenes are syn, anti, or mixed. For example, trifluoromethyl hypochlorite adds to alkenes and one may propose the mechanisms in Equations 4.2,4.3, and 4.4. 

When this addition was carried out with pure a,s-2-butene, only the erythro product was obtained, and with pure trans-2-butene, only the threo product was obtained [6], If Equation 4.2 were the mechanism, a mixture would be expected if Equation 4.3 were the mechanism, the results would have been the opposite. Only Equation 4.4 is in accord with the stereochemical results, that is, a concerted (or nearly so) syn addition. 

In ehmination reactions, a similar comparison of the stereochemistry of starting materials and products can indicate syn, anti, or mixed processes. One method for changing the stereochemistry of a double bond includes halogenation to the dihalide followed by heating with sodium iodide to affect first an Sj 2 reaction and then anti-elimination, illustrated for one iodination product in Equation 4.5 [7]. Kinetic data support this sequence of reaction steps leading to the trans alkene as the only product. 

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Carbon-13 Heteronuclear Longitudinal Spin Relaxation for Geometrical (and Stereochemical) Determinations in Small or Medium Size Molecules... 

Two structures have been determined by X-ray diffraction for stereochemical determination. The structure of one enolate derived from Meyers oxazolidinone was reported <1996JA7429> as well as structure of (2S,5R,7aR)-5-(benzotriazol-l-yl)-3-phenyl[2,l-A]oxazolopyrrolidine which was obtained as only one diastereomer <1998TL1697, 1999JOC1979>. 

Reduction of 25 with NaBH4 results in the formation of the blue-violet mercapto-(Z)-enethione 121. The configuration was determined by H and NMR and stereochemical-determining NOEs in solution, and by X-ray crystallography in the solid state <1995T13247>. 

Jayasuriya H, Salituro GM, Smith SK, Heck JV, Gould SJ, Singh SB, Homnick CF, Holloway MK, Pitzenberger SM, Patane MA (1998) Complestatin to Chloropeptin I via a Quantitative Acid Catalyzed Rearrangement. Absolute Stereochemical Determination of Complestatin. Tetrahedron Lett 39 2247... 

Because of all of the above pitfalls, NOE is probably the most misinterpreted experiment in organic chemistry. In my experience, /-coupling measurements, both homonuclear and heteronuclear, give far more reliable information than NOE measurements in the determination of small-molecule stereochemistry. To use NOE measurements for stereochemical determinations, it is always best to do the NOESY experiment on both isomers and compare the crosspeak intensities (relative to the diagonal peak intensities) and measure distances on both isomers using an energy-minimized computer model of the structures. If the differences in distance and NOE intensity are small between the two isomers, the experiment cannot be conclusive. 

The coupling is to the green proton in each case and the dihedral angles are 180° for the trans compound but only 60° for the cis one, so the smaller coupling belongs to the cis compound. We shall discuss below why the absolute values are so low this example illustrates how much easier stereochemical determination is if you have both stereoisomers to compare. 

Cichewicz RH, Clifford LJ, Lassen PR, Cao X, Freedman TB, Nafie LA, Deschamps JD, Kenyon VA, Flanary JR, Holman TR, Crews P (2005) Stereochemical determination and bioactivity assessment of (S)-(l)-curcuphenol dimers isolated from the marine sponge Didiscus aceratus and synthesized through laccase biocatalysis. Bioorg Med Chem 13 ... 

Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3 -disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [24-27]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2 1 mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. 

M. Suzuki, M.D. Allen, N. Yagi and J.T. Finch. Analysis of co-crystal structures to identify the stereochemical determinants of the orientation of TBP on the TATA box. Nucleic Acids Res. 24 (1996) 2767-73. 

Viderson, J. C., Whiting, M. Total Synthesis of ( )-Kainic Acid with an /tza-[2,3]-Wittig Sigmatropic Rearrangement as the Key Stereochemical Determining Step. J. Org. Chem. 2003, 68, 6160-6163. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Caldwell,). Stereochemical determinants of the nature and consequences of drug metabolism, J. Chromatogr. A, 1995, 694, 39—48. 

The total synthesis of nakienone A was reported by Negishi in 1997. Negishi s synthesis used a Pd-mediated cross-coupling reaction to install the pentadiene functionality on the cyclopentene ring. The total synthesis not only proved the original stereochemical determinations to be correct but also represented a facile method for the synthesis of the entire series of natural compounds as well as analogues for structure activity relationship (SAR) studies. 

Although a model was proposed in which olefin insertion occurred to place the metal on the terminus of the alkene ( 1,2-addition ) [10, 26], based upon subsequent mechanistic and synthetic studies of the hydrosilylation reaction of styrenes (see below), this model would appear to be incorrect [27]. Thus an irreversible, stereochemically determinant 2,1-insertion probably initiates the reaction, with subsequent o-bond metathesis completing the process. Most remarkable is the fact that, if correct, this model demands that the olefin insertion takes place to orient the highly hindered metal center at a tertiary carbon center, and that apparently little, if any, P-hydride elimination occurs from the resultant organometallic. 

Matsumori, N., Kanono, D., Murata, M., Nakamura, H., and Tachibana, K. (1999). Stereochemical determination of acyclic structures based on carbon-proton spin-coupling constants. A method of configuration analysis for natural products. J. Org. Chem. 64, 866-876. 

Menche, D., Arikan, F., Perlova, O., Horstmann, N. et al (2008) Stereochemical determination and complex biosynthetic assembly of etnangien,... 

The Scheidt group reported a highly diastereo- and enantioselective NHC-catalyzed reaction of a,p-unsaturated aldehydes with nitrones to afford y-amino esters. It is postulated that a rare six-membered heterocycle is generated as the initial product of the reaction, which gives the final y-amino ester product upon the addition of an alcohol. The mechanism for this reaction involves the addition of the homoenolate equivalent to the nitrone as the stereochemical-determining step, and catalyst turnover is promoted by an intramolecular acylation after the tautomerization of enol to acyl azolium (Scheme 7.60). 

The stereochemical determination of alkanes and cycloalkanes is always more difficult than that of functionalized organic molecules. For most methods, such as optical rotation measurements or X-ray crystallography, an isolated adequate amount of a single compound is required. It was also shown that for acyclic isopranes (terpanes) the specific optical rotation values are very low, virtually invalidating the use of polarimetry. 

For the stereochemical determination, it seemed theoretically that the most efficient method of separation for the three pristane isomers A, B and C would be direct gas chromatography on an optically active stationary phase. Such a method was successfully employed for amino acids and amine enantiomers . However, this method was found ineffective for pristane, and hence various gas-chromatographic inactive stationary phases were employed for the separation of the diastereoisomers. The relative stereochemistry could be determined, provided standards with known respective stereochemistry are available. 

Combining multiple spin-coupling constants for stereochemical determinations... 

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